A personalised intervention programme aimed at improving adherence to oral antidiabetic and/or antihypertensive medication in people with type 2 diabetes mellitus, the INTENSE study: study protocol for a randomised controlled trial

Background Medication non-adherence is a prevalent health problem in people with type 2 diabetes mellitus (T2DM). Interventions have previously been developed to improve medication adherence, but inconsistent outcomes have been reported. A potential explanation for this inconsistency is a ‘one size fits all’ approach, with interventions not tailored to the needs and preferences of individuals. Therefore, the aim of this study is to evaluate the effectiveness of a personalised intervention programme aimed at improving adherence to oral antidiabetic and/or antihypertensive medication in people with T2DM. Methods A parallel-group randomised controlled trial will be conducted in 40–50 community pharmacies in the Netherlands and the United Kingdom (UK). A total of 300 participants will be included and followed up for a period of 6 months. Participants will be people with T2DM identified as non-adherent to oral antidiabetic and/or antihypertensive medication, aged 35–75 years and mobile phone users. The intervention group will receive a personalised intervention programme that is based on one or more of the participants’ pre-defined non-adherence profile(s), namely (I) Knowledge and perceptions, (II) Practical problems, (III) Side effects and (IV) Negative mood and beliefs. The intervention comprises of one or more supporting modules, namely (I) Brief messaging, (II) Clinical medication review, (III) Medication schedule, (IV) Reminding messaging, (V) Medication dispensing systems, (VI) Smart messaging, (VII) Referral to general practitioner and (VIII) Unguided web-based Self Help Application for low mood. The control group will receive usual care including access to a publicly available informative diabetes website. The primary study outcome is medication adherence measured with a telephone pill count. Secondary outcomes are systolic blood pressure, HbA1c level, self-reported medication adherence, attitude and beliefs toward medication, satisfaction with diabetes treatment, health status and medical consumption and productivity cost. In addition, a process evaluation will be undertaken to establish the fidelity, reach and the extent to which intervention delivery is normalised in the daily practice of community pharmacy teams. Discussion The study can lead to a personalised intervention programme that improves medication adherence in people with T2DM that are non-adherent to oral antidiabetic and/or antihypertensive medication. Trial registration Dutch Trial Register, Trial NL8747, registered 02 July, 2020; ISRCTN Registry, ISRCTN36009809, registered 05 February, 2020. Supplementary Information The online version contains supplementary material available at 10.1186/s13063-022-06491-7.

. Brief description of the supporting modules

Brief messaging
Evalan platform(4) It has been shown that the use of brief SMS messages can result in an improvement of medication adherence in people with T2DM(5, 6) and in people using high blood pressure medication (7).
For the brief messaging module, brief educational messages with a fixed length of 160 characters were developed. The messages were developed in three brainstorm sessions with researchers and people working within a GP practice and evaluated by three patient panels in the Netherlands consisting of people with T2DM. The messages were developed within several domains of the Behavioural Change Technique Taxonomy by Michie (8). All messages that were approved by at least one panel were sent to the research team in the UK. After translation they were discussed in a patient panel in the UK and suggestions for change were made by the UK research team. The rephrased UK suggestions were again discussed within the research team of both countries until consensus was reached. In total 48 messages covering, according to the research teams of both countries, 12 domains of the Behavioural Change Technique Taxonomy by Michie et al. (8) were selected and put in a fixed order, so that participants will receive a wide range of informational issues on diabetes and diabetes medication covering the domains of the taxonomy without too much chronological overlap. Participants will receive either one or two text messages per week for a period of six months. Table A5. provides an indication of the content of the brief messages and their classification into the Behavioural Change Technique Taxonomy by Michie (8).
Participants will receive reminding text messages. During the consultation the pharmacist and participant decide at which time points the participants would like to receive reminding messages. Participants thereafter receive a reminding message at the time point they have indicated. The English version of the reminder message is: "This is a reminder to take your medicines."

Smart messaging
Evalan platform and electronic medication container (4,11) Text messaging including real time medication monitoring (smart messaging) has been shown to increase medication adherence (9). In a trial with T2DM patients the average medication adherence of patients who received smart reminding was found to increase from about 60% before the start of the trial to about 80% (12,13).
The participant will receive an electronic medication container that is linked to the Evalan platform. This combination of container and platform has been used in previous studies (12,14) At baseline, the participant and pharmacist include the time points at which the participant should take their medication. In case of smart messaging the electronic medication container will send a signal to the platform if opened. A participant is reminded via a text message if the medication is not taken within the predefined time frame (i.e. the medication container is not opened). Reminders are not send if the medication is taken as prescribed (i.e. the medication container is opened).

Clinical medication review
Pharmacist Medication adherence is related to multiple interrelating factors in several domains (15). Previously we have shown in people who were taking antihypertensive medication that personal beliefs, practical issues and side effects are important factors in medication adherence and that interventions to improve medication adherence should be tailored to the individual patient(16, 17). A clinical medication review by a pharmacist is ideally suited to address issues and to address medicated related problems. Also it has been shown that the most effective interventions to improve medication adherence were delivered face-to-face, by pharmacists, and administered directly to patients (18). This explains that the option of a clinical medication review is offered to the participants in all non-adherence profiles.
The pharmacist performs a clinical medication review in cooperation with the GP. In the Netherlands, this review will be performed according to a standard process as provided in the 'Multidisciplinary Guidelines for Polypharmacy' (19).
In short, the review consists of the following five steps: (I) Pharmacotherapeutic anamnesis, (II) Pharmacotherapeutic analysis, (III) Consultation GP and pharmacist, (IV) Feedback to participant and other care providers, and (V) Followup (19). In the UK, this review will be tailored to individual need and guided by the principles of 'A guide to medication review' (20).

Medication schedule
Pharmacist A medication schedule can be provided by the pharmacist, by using the pharmacy administration and information system. A medication schedule includes the (general) time points at which the participant should take their medication and the amount.

Pharmacist
Several studies indicate the potential of pill packaging and the use of a pillbox for improving medication adherence (21,22). Moreover, the study of Porter et al. showed a clinically significant decrease in systolic blood pressure, by 10 mmHg, in uncontrolled hypertensive patients that use a pillbox and got an instruction on the use(23).
Currently, several medication dispensing systems are available within the pharmacy. Examples of such systems are pill packaging, pillboxes and repeat dispensing service. The pharmacist will discuss with the participant which systems are available and provides the option(s) that comply with the needs of the participant.

Unguided web-based Self
Help Application for low mood Minddistrict platform (24) Depressive mood has been found to be related to poor treatment adherence (25,26). In the past years we have developed a web-based depression intervention for people with diabetes based on Cognitive Behavior Therapy (27) .
This guided self-help program ("Betergestemd") proved to be effective in reducing depressive symptoms as well as diabetes distress (28). This program runs on pc's, tablets and smart phones and recently has been further developed to an unguided self-help application ("myDiaMate") which aims to prevent and reduce psychological distress and fatigue in adults with diabetes. The content of "Betergestemd" is incorporated in a specific module on low mood, next to topics on diabetes in balance and fatigue (29). This unguided self-help application was found to be feasible and appreciated by people with diabetes to improve their psychological well-being.
In this project we shall offer this unguided version of "Betergestemd" to participants with an indication of low mood based on the WHO-5 questionnaire. The WHO-5 has proven to be a feasible screener for low mood (< 50) and likely depression (score ≤ 28)(2). Those who screen positive for likely depression will be prompted to make an appointment with their GP and the GP will be informed by the research group.
The Unguided web-based Self Help Application for low mood for people with diabetes consists of eight modules.
Modules focus on six techniques based on cognitive behavioral therapy: (I) pleasant activity scheduling, (II) cognitive restructuring, (III) relaxation, (IV) communication, (V) coping with worries, and (VI) assertiveness. The modules consist of text and exercises. In addition, participants are asked to keep a mood and relaxation diary. Participants will be advised to complete one module per week.
For use in the UK the Dutch version of the Unguided web-based Self Help Application for low mood was translated independently by two native English speakers who were living in the Netherlands and fluent in Dutch and discrepancies were discussed and solved. After this, the program was tested, commented on and adapted by a team of patient and public members working with the research team in the UK.

Referral to a GP
Pharmacist and GP There are two cases in which the pharmacist will refer the participant to the GP.

Side effects
When a participant indicates to experience side effects a clinical medication review will be carried out first.
When the side effects cannot be resolved by this medication review the participant will be referred to their GP for a regular consult.

Very low mood
We will screen for low mood by using the Adapted QBS. In the Adapted QBS questions of the WHO-5 questionnaire are incorporated. The WHO-5 questionnaire has a score ranging from 0-100. All participants in the intervention group that score ≤50, and that are not receiving any form of psychotherapy, will be offered the Unguided web-based Self Help Application for low mood. All participants, both in the intervention and control group, with a score ≤ 28 will be advised to visit their GP to screen for depression. The GP will be informed of this advice. Repetition and substitution + Antecedents +

Week 3
Monday: Making a list of points to discuss before any appointment is a really good use of your time and means you don't forget anything.

Regulation
Thursday: Diabetes UK has a great website (https://www.diabetes.org.uk/home) and a helpline (0345 123 2399) which may be of help.

Week 4
Monday: You will experience fewer side effects if you take your medicines regularly. Consequences + Natural consequences Thursday: You are not alone, many people forget to take their medicines. Shaping knowledge